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Project description:ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including liver cancer. Previous studies have demonstrated that ARID1A deficiency can cause liver cancer metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms remain poorly understood. To address the effect of Arid1a deficiency on chromatin organization, we generated chromatin interaction matrices, and exploited the conformation changes upon Arid1a depletion in hepatocytes. Our results demonstrated that Arid1a deficiency induced A/B compartment switching, topologically associated domain (TAD) remodeling, and decrease of chromatin loops. Further mechanism studies revealed that ATPase BRG1 of SWI/SNF complex could physically interact with RAD21, a structural subunit of chromatin architectural element cohesin; whereas ARID1A deficiency significantly diminished the coupled BRG1-RAD21. Interestingly, the tumor-associated genes within the switched compartments were differentially expressed depending upon Arid1a depletion or not. As a consequence of ARID1A deficiency-induced conformational alteration, the dysregulation of some genes such as PMP22 and GSC, promoted the invasion capacity of liver cancer cells. This study provides an insight into liver cancer tumorigenesis and progression related to ARID1A mutations.
| S-EPMC8542038 | biostudies-literature
Project description:ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including hepatocellular carcinoma (HCC). Previous studies have demonstrated that ARID1A deficiency can cause HCC metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms of which remain poorly understood. Whether and how SWI/SNF complex could function as an architectural cooperator to synergistically stabilize chromatin organization should be explored, particular in tumorigenesis. Here we reveal that SWI/SNF complex acts as a potential architectural cooperator via BRG1-RAD21 axis for chromatin organization maintenance; ARID1A deficiency weakens the interaction and thus loosens chromatin compactness, which drives HCC metastasis dependent on the conformational dysregulation on some key genes.
2020-08-24 | GSE152050 | GEO
Project description:ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including hepatocellular carcinoma (HCC). Previous studies have demonstrated that ARID1A deficiency can cause HCC metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms of which remain poorly understood. Whether and how SWI/SNF complex could function as an architectural cooperator to synergistically stabilize chromatin organization should be explored, particular in tumorigenesis. Here we reveal that SWI/SNF complex acts as a potential architectural cooperator via BRG1-RAD21 axis for chromatin organization maintenance; ARID1A deficiency weakens the interaction and thus loosens chromatin compactness, which drives HCC metastasis dependent on the conformational dysregulation on some key genes.
2020-08-24 | GSE152049 | GEO
Project description:ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives HCC metastasis
| PRJNA642980 | ENA
Project description:ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives HCC metastasis [RNA-seq]
| PRJNA659143 | ENA
Project description:ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives HCC metastasis [ChIP-seq]
| PRJNA638150 | ENA
Project description:Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.
| S-EPMC8677624 | biostudies-literature
Project description:SMARCAL1 and BRG1, both classified as ATP-dependent chromatin remodeling proteins, play a role in double-strand break DNA damage response pathways. Mutations in SMARCAL1 cause Schimke Immuno-osseous Dysplasia (SIOD) while mutations in BRG1 are associated with Coffin-Siris Syndrome (CSS4). In HeLa cells, SMARCAL1 and BRG1 co-regulate the expression of ATM, ATR, and RNAi genes on doxorubicin-induced DNA damage. Both the proteins are found to be simultaneously present on the promoter of these genes. Based on these results we hypothesized that SMARCAL1 and BRG1 interact with each other forming a complex. In this paper, we validate our hypothesis and show that SMARCAL1 and BRG1 do indeed interact with each other both in the absence and presence of doxorubicin. The formation of these complexes is dependent on the ATPase activity of both SMARCAL1 and BRG1. Using deletion constructs, we show that the HARP domains of SMARCAL1 mediate interaction with BRG1 while multiple domains of BRG1 are probably important for binding to SMARCAL1. We also show that SIOD-associated mutants fail to form a complex with BRG1. Similarly, CSS4-associated mutants of BRG1 fail to interact with SMARCAL1, thus, possibly contributing to the failure of the DNA damage response pathway and pathophysiology associated with SIOD and CSS4.
| S-EPMC9243424 | biostudies-literature
Project description:A mouse strain expressing an Rb-binding deficient mutant of FoxM1, FoxM1 DD, develops PyMT-driven mammary tumors that are deficient in metastasis. Single-cell RNA-Seq analyses revealed altered tumor microenvironment (TME). Unlike the FoxM1 +/+ tumors, the FoxM1 DD/DD tumors lack tumor-infiltrating cells, resulting from a deficiency in the tumor cell-populations that express factors necessary for their recruitment. Furthermore, FoxM1 DD/DD tumors contain fewer mammary cancer stem/progenitor cells, but more differentiated tumor cells.
2024-06-20 | GSE178612 | GEO
Project description:BRG1 and BRM, central components of the BAF (mSWI/SNF) chromatin remodelling complex, are critical in chromatin structure regulation. Here, we show that the human BRM (hBRM) bromodomain (BRD) has moderate specificity for H3K14ac. Surprisingly, we also find that both BRG1 and hBRM BRDs have DNA-binding activity. We demonstrate that the BRDs associate with DNA through a surface basic patch and that the BRD and an adjacent AT-hook make multivalent contacts with DNA, leading to robust affinity and moderate specificity for AT-rich elements. Although we show that the BRDs can bind to both DNA and H3K14ac simultaneously, the histone-binding activity does not contribute substantially to nucleosome targeting in vitro. In addition, we find that neither BRD histone nor DNA binding contribute to the global chromatin affinity of BRG1 in mouse embryonic stem cells. Together, our results suggest that association of the BRG1/hBRM BRD with nucleosomes plays a regulatory rather than targeting role in BAF activity.
| S-EPMC5519978 | biostudies-literature